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Ecology and epidemiology
Chikungunya virus CHIKV is a mosquito-borne virus responsi-
ble for periodic and explosive outbreaks of a febrile disease that
is characterized by severe and sometimes prolonged polyarthritis.
CHIKV was irst recognized as a human pathogen after it was iso-
lated from the serum of an infected patient during an outbreak of
debilitating arthritic disease in in present-day Tanzania .
Because of the stooped posture and rigid gait of infected individ-
uals, the disease was given the name chikungunya, a word from
the Kimakonde language that translates as “that which bends up”
. The vast majority of infected individuals develop chikungunya
fever, an acute illness notable for rapid onset of fever, incapaci-
tating polyarthralgia and arthritis, rash, myalgia, and headache
Table and ref. . Acute CHIKV disease symptomatically resem-
bles dengue fever, and retrospective case reports suggest that
CHIKV outbreaks occurred as early as but were inaccurately
attributed to dengue virus , . However, unlike dengue, a char-
acteristic feature of CHIKV disease is recurring musculoskeletal
disease primarily affecting the peripheral joints that can persist
for months to years after acute infection . CHIKV disease
is often self-limiting and has a low fatality rate ~. , but
manifestations of CHIKV infection that lead to acute and chronic
disability have considerable implications, including a substantial
impact on quality of life for infected patients as well as consider-
able economic and community consequences , , .
Transmission of CHIKV occurs mainly through the bite of an
infected Aedes subgenus Stegomyia species of mosquito. However,
maternal-fetal transmission can occur intrapartum, which results
in high rates of infant morbidity , . Historically, CHIKV has
been endemic in tropical and subtropical regions of sub-Saharan
Africa and Southeast Asia, where two distinct CHIKV transmission
cycles exist. CHIKV is maintained in a rural enzootic transmis-
sion cycle, which occurs between various forest or savannah Aedes
Stegomyia mosquitoes and animal reservoirs , with nonhu-
man primates being the presumed major reservoir host , .
Occasional introduction of the virus into urban areas is thought to
cause periodic outbreaks of CHIKV disease , . Urban trans-
mission is mediated primarily by Aedes aegpti or Aedes albopictus
mosquitoes and occurs in a human-mosquito-human transmis-
sion cycle . While enzootic sylvan transmission of CHIKV
has been well established in Africa, outbreaks in Asia have been
mainly attributed to urban human-mosquito-human transmission,
although there is limited evidence for enzootic transmission ,
. Little is known about the factors contributing to the natu-
ral maintenance of CHIKV , , , , but understanding cata-
lysts that promote CHIKV maintenance and spillover dynamics is
essential to combatting emergence and spread of the virus.
Since the irst reports of CHIKV infection in Africa in the s,
subsequent epidemics of CHIKV occurred throughout the latter half
of the th century in countries within Asia and sub-Saharan Africa
Figure and reviewed in ref. . Phylogenetic analyses of CHIKV
sequences indicate that CHIKV originated in Africa over years
ago , and a common lineage diverged into two distinct branch-
es, termed West African WA and East/Central/South African
ECSA . WA strains have been associated mainly with enzo-
onotic transmission and small focal outbreaks of human disease in
countries located in western Africa Figure and ref. . In con-
trast, strains from the ECSA lineage have repeatedly spread to new
regions to cause signiicant urban epidemics. The irst emergence
of an ECSA strain outside of Africa is estimated to have occurred
between and years ago in Asia . The virus continued to
circulate in this area, evolving independently of the ECSA lineage
into a distinct Asian genotype , which has caused numerous
outbreaks of CHIKV disease in this region Figure and ref. .
An ECSA strain emerged again during an outbreak in Kenya
in late , initiating one of the largest CHIKV epidemics on
record, with expansion to areas well beyond the historical range
of the virus , . During this devastating epidemic, the virus
spread to a number of islands in the Indian Ocean, India, and
parts of Southeast Asia, leading to over million estimated cases
Chikungunya virus (CHIKV), a reemerging arbovirus, causes a crippling musculoskeletal inflammatory disease in humans
characterized by fever, polyarthralgia, myalgia, rash, and headache. CHIKV is transmitted by Aedes species of mosquitoes and
is capable of an epidemic, urban transmission cycle with high rates of infection. Since 2004, CHIKV has spread to new areas,
causing disease on a global scale, and the potential for CHIKV epidemics remains high. Although CHIKV has caused millions of
cases of disease and significant economic burden in affected areas, no licensed vaccines or antiviral therapies are available. In
this Review, we describe CHIKV epidemiology, replication cycle, pathogenesis and host immune responses, and prospects for
effective vaccines and highlight important questions for future research.
Chikungunya virus: epidemiology, replication, disease
mechanisms, and prospective intervention strategies
Laurie A. Silva and Terence S. Dermody
Department of Pediatrics, University of Pittsburgh School of Medicine, Children’s Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
Conflict of interest: The authors have declared that no conflict of interest exists.
Reference information: J Clin Invest. 2017;127(3):737–749.
https://doi.org/10.1172/JCI84417.
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Like that of the ECSA lineage, the geographical range of the
Asian lineage has also recently expanded. Since , when the
virus was irst detected in the Paciic Island region of New Cale-
donia , CHIKV has caused outbreaks on of the coun-
tries and territories of the Paciic Islands, with strains from the
Asian lineage being responsible for the majority of these out-
breaks , . Beginning in , islands in Oceania were bom-
barded with not only CHIKV outbreaks, but also epidemics of
Dengue virus and Zika virus , , . As with CHIKV, infect-
ed travelers are thought to be the main source of Dengue and
Zika virus outbreaks in the Paciic. Strains from the Asian and
ECSA lineages, including the IOL subgroup, continue to cocircu-
late and spread within the Indian subcontinent, Southeast Asia,
and Oceania Figure and refs. , , .
With such high rates of virus importation by infected travelers,
the introduction of CHIKV into the Western Hemisphere seemed
inevitable. In December , the irst local transmission of
CHIKV in the Western Hemisphere in modern history was report-
ed, with autochthonous cases identiied in the Caribbean island
of French St. Martin . The emergence of CHIKV in the West-
ern Hemisphere was remarkable in that the virus spread rapidly
to immunologically naive populations in the Caribbean as well as
Central, South, and North America. Since the introduction
of CHIKV in the Americas, over million suspected cases caused
by endemic transmission have occurred in almost countries,
including cases of autochthonous transmission in the United
States Figure and ref. . The initial outbreak of CHIKV in the
Americas was irst attributed to a variant from the Asian lineage.
However, the introduction of an ECSA strain into Brazil in
raises a concern for vector adaptation in the Americas and
spread of CHIKV to more temperate regions, such as the United
States, where A. albopictus has a greater range Figure and ref.
. Because of globalization and the expansion and year-round
presence of relevant vectors, especially in densely populated
urban centers , the risk that the virus will become endemic in
tropical regions of the Americas remains high. Establishment of
CHIKV in the Americas, as well as repeated introduction events,
suggests that the virus will continue to spread and that the sporad-
ic and explosive outbreaks of CHIKV observed in Africa and Asia
also will likely occur in the Western Hemisphere.
CHIKV structure, genome, and replication cycle
CHIKV is a small ~ nm in diameter, enveloped virus that is a
member of the Old World Semliki Forest virus group of arthrito-
genic alphaviruses within the Togaviridae family reviewed in ref.
. The CHIKV genome is approximately , nucleotides,
constituting a single-stranded, message-sense RNA with a ′
-methylguanosine cap and a ′ poly-A tail . The genome con-
tains two open reading frames ORFs separated by a noncoding
junction as well as ′- and ′-untranslated regions , . Four
essential nonstructural proteins nsP, , , and constitute the
RNA replicase Table and are encoded by the ′ two-thirds of the
genome , . The ′ ORF is translated from a subgenomic pos-
itive-strand mRNA and encodes six proteins Table , including
three major structural proteins capsid, E, and E , .
The CHIKV virion is formed by a lipid bilayer envelope tightly
associated with an icosahedral nucleocapsid shell capsid
of CHIKV disease Figure and refs. , , , . International
air travel greatly facilitated the geographic expansion of CHIKV
during this epidemic , with viremic travelers importing
an unprecedented number of CHIKV cases into naive countries,
including more temperate regions in Europe and the United States
, , . Infected travelers often served as sentinels, seeding
autochthonous transmission of the virus in naive areas, including
in Italy in and France in .
Historically, urban transmission of CHIKV was vectored
mainly by A. aegpti mosquitoes. However, many of the recent
outbreaks in the Indian Ocean basin and Southeast Asia have been
attributed to circulating strains from the Indian Ocean lineage
IOL, a newly emerged subgroup within the ECSA clade .
Some strains within this subgroup contain an adaptive mutation
EAV that increases viral itness in A. albopictus without
compromising replication in A. aegpti . This mutation
has been selected convergently in multiple ECSA strains in dif-
ferent geographic regions during the past decade , , .
Importantly, the EAV substitution requires epistatic interac-
tions EA and ET to allow penetrance in A. albopictus
reviewed in ref. . These epistatic variants are lineage-specif-
ic, as they have been observed in other ECSA and WA strains but
not in strains from the Asian lineage, rendering viruses from the
Asian clade genetically constrained in the capacity to adapt to A.
albopictus . Additional substitutions in viral glycoproteins also
augment replicative capacity in A. albopictus reviewed in ref. .
Table 1. Typical and atypical manifestations of CHIKV disease
in patients
Organ/System Typical Atypical
Systemic Fever; asthenia Lymphadenopathy
Musculoskeletal Arthralgia; arthritis;
myalgia; joint edema;
tenosynovitis; backache;
persistent or relapsing-
remitting polyarthralgias
Chronic inflammatory rheumatism;
articular destruction
Dermatological Rash; erythema Bullous dermatosis;
hyperpigmentation; stomatitis;
xerosis
Neurological Headache Meningoencephalitis;
encephalopathy; seizures;
sensorineural abnormalities;
Guillain-Barré syndrome; paresis;
palsies; neuropathy
Gastrointestinal Nausea; vomiting; abdominal pain;
anorexia; diarrhea
Hematological Lymphopenia;
thrombocytopenia
Hemorrhage
Ocular Retro-orbital pain;
photosensitivity
Optic neuritis; retinitis; uveitis
Cardiovascular Myocarditis; pericarditis;
heart failure; arrhythmias;
cardiomyopathy
Hepatic Fulminate hepatitis
Pulmonary Respiratory failure; pneumonia
Renal Nephritis; acute renal failure
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with host proteins, form an early, short-lived viral replicase that
synthesizes a full-length negative-sense vRNA .
Negative-strand synthesis is linked to formation of viral repli-
cation compartments termed spherules, which are small, vesicu-
lar structures that form at the plasma membrane PM and serve
as the site of vRNA replication Figure . The nsPs are thought
to localize at the neck of the spherules, which house dsRNA inter-
mediates, protecting them from degradation and recognition by
cellular pattern-recognition receptors , . As infection
proceeds, spherules are internalized to form large cytopathic vac-
uoles CPVI, which contain markers from endosomal and lyso-
somal membranes Figure and refs. . P accumulation
leads to complete proteolytic processing of the polyprotein, result-
ing in a switch of the replicase to an abundant conformer that uses
negative-sense vRNA as a template for ampliication of genomic
positive-sense vRNA as well as transcription of a subgenomic,
positive-sense vRNA that encodes the structural polyproteins
capsid, E, E, K, TF, and E. Following translation of capsid
protein, autoproteolysis releases it from the structural polyprotein,
allowing interaction with newly synthesized genomes to catalyze
oligomerization and formation of intact nucleocapsids containing
a single molecule of the RNA genome Figure and ref. . Trans-
lation of the structural polyprotein continues, generating a major-
ity product, EEKE, and a minor product, EETF, due to
ribosomal frameshifting , . A signal sequence present at the
copies that encapsidates genomic RNA , . Embedded with-
in the viral envelope are heterodimers of the E and E glycopro-
teins arranged in trimers forming an icosahedral lattice .
Although the general events of CHIKV replication are compa-
rable to those of other alphaviruses Figure , much more remains
to be discovered about the speciic biology of CHIKV replication.
However, CHIKV displays broad tropism, replicating in many ver-
tebrate and invertebrate cells ; bona ide proteinaceous
receptors have not been identiied for CHIKV. Glycosaminogly-
cans, which are expressed on many susceptible cell types, appear
to serve as attachment factors to enhance infectivity , .
After E-mediated attachment to cells, receptor-bound particles
are internalized mainly by clathrin-mediated endocytosis Figure
and refs. , , . Endosomal acidiication triggers conforma-
tional changes in the viral glycoproteins, leading to exposure and
insertion of the buried E fusion loop into the host membrane,
which results in fusion of the viral envelope and endosomal mem-
brane . Following release into the cytoplasm, the nucleocapsid
disassembles to deliver genomic viral RNA vRNA into the cyto-
sol for translation . The incoming CHIKV genome is directly
translated to produce the nonstructural precursor polyprotein
P, which is cleaved by the virus-encoded protease located
in nsP into P and nsP , . Some strains encode an opal
stop codon following nsP, and low-frequency read-through yields
both P and P . Together, P and nsP, presumably
Figure 1. Geographic distribution of endemic CHIKV and its primary vectors, Ae. aegypti and Ae. albopictus. Countries in which autochthonous cases of
CHIKV have been reported are specified with colored symbols representing the distinct viral genotypes detected during outbreaks in that country. West
African strains are indicated by purple triangles; Asian strains are indicated by green circles; East/South/Central African (ESCA) strains are indicated with
blue squares; strains of the Indian Ocean lineage, a subtype of the ESCA clade, are indicated with blue squares with a cross; and strains whose genotype
has not been determined are indicated with gray diamonds. Symbols are shaded to differentiate transmission prior to (darker hue) or after (lighter hue)
the reemergence of the virus in the Indian Ocean (ECSA strain in 2005) and Pacific Islands (Asian strain in 2010). Symbols indicate the countries in which
natural transmission has occurred and are not meant to indicate precise locations of outbreaks. Overlayed with CHIKV distribution is the geographic range
of the two primary vectors responsible for urban mosquito-human-mosquito transmission of the virus. Range of Ae. aegypti is indicated in red; range of
Ae. albopictus is indicated in yellow; and areas where both mosquito species are present are indicated in orange. Endemic CHIKV data were obtained from
numerous PubMed publications (1, 3, 23, 24, 28, 30–32, 37, 38, 46–62). Range of mosquito data was obtained from (63).
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CHIKV are areas of active research. A comprehensive understand-
ing of the CHIKV replication cycle in both mammalian and mosqui-
to cells is essential for development of effective antivirals.
Disease mechanisms and host immune
responses
Studies of CHIKV-infected humans and animals have deined
symptoms and immune responses of acute and chronic CHIVK dis-
ease, but much of the molecular interplay between virus and host
remains to be established. CHIKV-induced disease shares many
similarities with illnesses caused by other arthritogenic alphavi-
ruses, with some distinctions observed reviewed in refs. .
After deposition into the bloodstream or skin through a bite of an
infected mosquito, CHIKV replicates at the site of inoculation in
ibroblasts and possibly macrophages Figure and refs. , , ,
. Despite triggering innate immune responses, the virus spreads
via lymphatics into the bloodstream, allowing dissemination to sev-
eral sites of replication, most commonly lymphoid organs lymph
nodes and spleen, skin, and especially tissues where prominent
disease symptoms occur muscle, peripheral joints, and tendons
but also in brain and liver in more severe cases , . Rep-
lication of CHIKV in peripheral tissues results in remarkably high
serum viral loads
virus particles/ml; ref. . Such high-level
viremia in humans is rare for most alphaviruses and allows CHIKV
to be easily transmitted to mosquitoes via a bloodmeal.
Acute CHIKV infection elicits robust innate immune responses,
leading to elevation of type I IFNs and numerous proinflammatory
chemokines, cytokines, and growth factors Table and refs. ,
. Type I IFN signaling controls viral replication and patho-
genesis during acute infection , . In humans, IFN-α
appears early in infection and correlates with viral load , ,
. Coincident with rising viral loads and IFN-α responses, the
vast majority of infected patients experience sudden onset of clini-
cal illness Table , with a small proportion of infected individuals
– remaining asymptomatic , . Acute CHIKV infec-
tion is predominated by high fever °C°C, which can last up
N-terminus of E trafics the major and minor structural polypro-
teins through the host secretory pathway, where cleavage by host
proteases produces pE EE; K or transframe TF; and E.
K and TF are viral accessory proteins that share an N-terminus
but have disparate C-termini, resulting from ribosomal frame-
shifting, and are hypothesized to form ion channels . Although
K and TF are found at low levels in virion particles , ,
and appear to contribute to viral budding , and pathogen-
esis , their precise roles in glycoprotein processing, assembly,
budding, and particle stability remain to be clariied , , .
As E and EE transit the secretory pathway Figure , they
remain associated as a noncovalent, hetero-oligomeric complex
that undergoes conformational changes and posttranslational
modiications, including palmitoylation and N-linked glycosyla-
tion as well as release of E by furin, to form mature spikes at the
PM Figure and refs. , . Recruitment of intact nucleocap-
sids to membrane-associated envelope glycoproteins leads to PM
budding of assembled particles . Late in infection, a second
type of virally induced cytopathic vacuole, CPVII, is formed Fig-
ure . These structures contain helical tubular arrays of viral gly-
coproteins within the vesicles, which are studded with nucleocap-
sids on their cytoplasmic face . Their proximity to the PM
suggests that CPVIIs may be an assembly intermediate , but
it is not clear whether they are necessary for eficient infection or
contribute to pathogenesis. CHIKV CPVI and CPVII structures
also have been observed in mosquito cells .
Infection of mammalian cells with CHIKV leads to massive
changes, including antiviral responses e.g., apoptosis, IFN, stress
granule formation, and unfolded protein response and proviral
responses e.g., host cell shutoff and authophagy . CHIKV
nsP and nsP display activities that counteract some of these anti-
viral responses . Authophagy is proposed to play a global pro-
CHIKV function in human cells, possibly by limiting apoptosis, and
may be a pathogenesis determinant . Although some addi-
tional proviral host factors have been identiied , , , ,
speciic host pathways and mechanisms that promote replication of
Table 2. CHIKV proteins and functions
Protein Size (aa) Function
Nonstructural proteins
nsP1 535 Methyltransferase and guanylyltransferase activity that caps viral RNA; sole membrane anchor for replicase complex
nsP2 798 N-terminal NTPase, helicase, and RNA triphosphatase activities; C-terminal cysteine protease activity responsible for processing of
nonstructural polyprotein
nsP3 530 Phosphoprotein with unknown functions, but important for minus-strand synthesis; contains macro domain and SH3-binding regions; likely
interacts with host proteins
nsP4 611 RNA-dependent RNA polymerase (RdRp); putative terminal transferase activity
Structural proteins
Capsid 261 Encapsidates genomic RNA to form nucleocapsid core; carboxyl domain is an autocatalytic serine protease
pE2 487 Intermediate composed of E3 and E2; cleaved by host furin protease
E3 64 N-terminal domain is uncleaved leader peptide for E2; may help shield fusion peptide in E1 during egress
E2 423 Mediates binding to receptors and attachment factors on cell membrane; major target of neutralizing antibodies
6K 61 Leader peptide for E1; putative ion channel; may enhance particle release
TF 76
Transframe protein generated by ribosomal frameshifting; shares N-terminus with 6K; putative ion channel; may enhance particle release
E1 439 Type II fusion protein; mediates fusion of viral envelope and cellular membrane via fusion peptide
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. In recent epidemics, more atypical and severe symptoms have
been observed, including multiple dermatological manifestations,
hemorrhage, hepatitis, myocarditis, neurological disorders, and
ocular disease Table and refs. , . Atypical symptoms
are most prevalent among vulnerable groups, including neonates,
the elderly, and those with underlying comorbidities.
to a week and may occur in a biphasic manner , . After fever
onset, most patients develop severe and often debilitating polyar-
thralgia that is usually bilateral and symmetric, most commonly in
ankles, wrists, and phalanges. Other symptoms include arthritis,
asthenia, conjunctivitis, gastrointestinal distress, headache, myal-
gia, and rash, which is usually maculopapular and pruritic Table
Figure 2. CHIKV replication cycle in mammalian cells. (i) E2 binds to the cell surface via an unknown receptor and possibly glycosaminoglycans as
attachment factors. (ii) CHIKV enters the cell through clathrin-mediated endocytosis. Acidification of endosomes leads to insertion of the fusion peptide
in E1 into the endosomal membrane. (iii) Fusion of the viral envelope and endosomal membrane releases nucleocapsid into the cytosol. (iv) Disassembly
of the nucleocapsid liberates positive-sense genomic RNA and nonstructural protein (nsP) translation occurs. (v) Four nsPs, together with genomic RNA
and presumably host proteins, assemble at the plasma membrane (PM) and modify it to form viral replication compartments (spherules) containing viral
dsRNA. nsP1–4 function as a replicase and localize to the spherule neck to generate genomic, antigenomic, and subgenomic vRNAs. (vi) Spherule internal-
ization allows formation of large cytopathic vacuoles (CPV-1) that house multiple spherules. Spherules at the PM or within CPV-I are fully functional. (vii)
Translation of subgenomic RNA produces the structural polyprotein, and capsid autoproteolysis releases free capsid into the cytoplasm. Translocation of
E3-E2-6K-E1/E2-E2-TK polyproteins into the ER. E2/E1 are posttranslationally modified, transit the secretory system, and are deposited at the PM. (viii)
Interaction of capsid and genomic RNA leads to formation of icosahedral nucleocapsids. (ix) Nucleocapsids assemble with E2/E1 at the PM, resulting in
budding of mature progeny virions. (x) Later in infection, CPV-IIs form, containing hexagonal lattices of E2/E1 and are studded with nucleocapsids. (xi)
CPV-IIs likely serve as transport vehicles and assembly sites for structural proteins, allowing formation of mature virions and egress.